A synaptic and circuit basis for corollary discharge in the auditory cortex

A synaptic and circuit basis for corollary discharge in the auditory cortex Schneider Nelson Mooney

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A synaptic and circuit basis for corollary discharge in the auditory cortex 2014 Nature 10.1038/nature13724 Schneider2014-a-synaptic-and-circuit-basis-for-corollary-d Schneider2014-a-synaptic-and-circuit-basis-for-corollary-d.txt, the project's staged copy d8ccb962503cefa40287be80ed30af22e0fde378 not-redistributable neuroscience

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0 spans located by searching the stored text for the quote's exact words, allowing any whitespace between them how a copy of the motor command reaches auditory cortex and what it does to hearing during movement Quotation withheld because this record is not cleared for redistribution. which synapses and which circuit carry the motor-related suppression of auditory cortical responses Quotation withheld because this record is not cleared for redistribution. identifies the suppression as postsynaptic inhibition from local PV interneurons, driven by a specific set of secondary motor cortex neurons that project to auditory cortex and fire before movement Quotation withheld because this record is not cleared for redistribution. mechanism Quotation withheld because this record is not cleared for redistribution. motor-related corollary discharge in auditory cortex Quotation withheld because this record is not cleared for redistribution. electrophysiology electrophysiology Quotation withheld because this record is not cleared for redistribution. mechanisms Motor-related signals from secondary motor cortex excite PV+ interneurons in auditory cortex, which postsynaptically inhibit excitatory cells and thereby suppress both spontaneous and sound-evoked activity Quotation withheld because this record is not cleared for redistribution. mechanisms Transient motor-driven dampening of sensitivity to self-predictable quiet sounds preserves headroom for responding to unexpected loud stimuli status: the paper's own words: may reflect Quotation withheld because this record is not cleared for redistribution. motor-related signals excite PV interneurons, which postsynaptically inhibit excitatory cells and suppress both spontaneous and evoked activity duplicate of: mechanisms[0] Quotation withheld because this record is not cleared for redistribution. the inhibitory cells fire well before movement onset and before the excitatory cells fall below baseline, in the order M2 then PV then excitatory Quotation withheld because this record is not cleared for redistribution. the movement-related voltage change reverses near the chloride equilibrium potential, which is what identifies the inhibition as postsynaptic Quotation withheld because this record is not cleared for redistribution. the suppression may dampen sensitivity to predictable quiet sounds while preserving responsiveness to unexpected loud ones Quotation withheld because this record is not cleared for redistribution. the mechanism differs from the disinhibition proposed for locomotion-driven gain increases in visual cortex Quotation withheld because this record is not cleared for redistribution. The evidence establishes postsynaptic inhibition but does not exclude a presynaptic contribution. what this limits: the mechanism of the suppression: the features INDICATE ... POSTSYNAPTIC INHIBITION, BUT DO NOT EXCLUDE THE POSSIBILITY THAT PRESYNAPTIC INHIBITION IS ALSO INVOLVED Quotation withheld because this record is not cleared for redistribution. Animals were not randomised to groups and investigators were not blinded to group allocation. what this limits: every group comparison in the paper: RANDOMIZATION WAS NOT USED TO DETERMINE HOW ANIMALS WERE ALLOCATED TO EXPERIMENTAL GROUPS, NOR WERE INVESTIGATORS BLINDED TO GROUP ALLOCATION Quotation withheld because this record is not cleared for redistribution. Optogenetic terminal stimulation could in principle recruit indirect pathways via antidromic activation (argued against by two control observations). what this limits: the terminal-stimulation results: OPTOGENETIC ACTIVATION OF M2 TERMINALS ... TRIGGERS ANTIDROMIC PROPAGATION ... AND THUS EXCITES OTHER TARGETS OF M2 ACtx CELLS Quotation withheld because this record is not cleared for redistribution. postsynaptic inhibition is established but presynaptic inhibition is not excluded outright duplicate of: limitations[0] · what this limits: the same scope as limitations[0] - postsynaptic inhibition is established, presynaptic is not excluded Quotation withheld because this record is not cleared for redistribution. M2 could also act indirectly through neuromodulatory cell groups, which the design does not rule out what this limits: the direct-pathway interpretation: M2 COULD ALSO ACT INDIRECTLY THROUGH OR IN CONCERT WITH NEUROMODULATORY CELL GROUPS Quotation withheld because this record is not cleared for redistribution. vocalizations were always accompanied by other movements, so no vocalization-specific signal could be isolated what this limits: any vocalisation-specific reading: VOCALIZATIONS WERE ALWAYS ACCOMPANIED BY OTHER HEAD AND BODY MOVEMENTS, and the membrane potential dynamics WERE INDISTINGUISHABLE FROM THOSE OBSERVED DURING HEAD MOVEMENTS Quotation withheld because this record is not cleared for redistribution. excitatory cells were identified by intrinsic and firing properties, with staining in only a subset what this limits: results reported by cell class: cells were CLASSIFIED AS PUTATIVE EXCITATORY CELLS BASED ON THEIR INTRINSIC PROPERTIES ... AND, IN A SUBSET OF NEURONS, INTRACELLULAR STAINING Quotation withheld because this record is not cleared for redistribution. corollary discharge as a framework, imported from systems where the motor copy is a single identified neuron Quotation withheld because this record is not cleared for redistribution. terminal stimulation used to bypass a pathway rather than to activate a region, isolating where an effect arises Quotation withheld because this record is not cleared for redistribution. randomisation of animals to experimental groups - NOT USED, and the paper says so eliminates: that a difference between groups is a difference in which animals were put in them · outcome (stated by the tagger, no quotation): absent-declared-unreported Quotation withheld because this record is not cleared for redistribution. blinding of investigators to group allocation - NOT USED, and the paper says so eliminates: experimenter expectancy in allocating and handling the animals · outcome (stated by the tagger, no quotation): absent-declared-unreported Quotation withheld because this record is not cleared for redistribution. blinding to movement/rest and laser on/off obtained from AUTOMATION rather than procedure - membrane potential mean and variance, tone-evoked responses and movement onset/offset all calculated automatically eliminates: the experimenter's judgement in scoring the conditions that carry the paper's main claim - the blinding the previous sentence says was not done by allocation is recovered here by taking the human out of the measurement · outcome (stated by the tagger, no quotation): held Quotation withheld because this record is not cleared for redistribution. corollary discharge here means a motor-related signal that PRECEDES movement, which is what distinguishes it from sensory reafference caused by the movement Quotation withheld because this record is not cleared for redistribution. the local share of the suppression is quantified rather than asserted: about 60 percent arises inside auditory cortex, the rest elsewhere in the pathway Quotation withheld because this record is not cleared for redistribution. M2 ACtx cells are a subset defined by their projection target, identified by an intersectional strategy, and behave like the general M2 population Quotation withheld because this record is not cleared for redistribution. movement here spans locomotion, head and body movements, grooming and vocalization, all producing indistinguishable auditory cortical dynamics Quotation withheld because this record is not cleared for redistribution. the head-fixed treadmill preparation was validated against the freely behaving one before being used for the optogenetics Quotation withheld because this record is not cleared for redistribution. claim_type: mechanism a second reading reaching the same value. Recorded: mechanism — note: a second reading reaching the same value from a different sentence. Not applied - a person decides. Quotation withheld because this record is not cleared for redistribution. method: sharp-electrode intracellular recording in freely behaving and head-fixed mice, with optogenetic activation and silencing, multielectrode arrays and two-photon imaging a second reading DIFFERING from the recorded value. Recorded: electrophysiology — note: a second reading, verbatim-verified, disagreeing with the value on the record. Not applied - a person decides. Quotation withheld because this record is not cleared for redistribution. phenomenon: suppression of auditory cortical responses before and during movement a second reading DIFFERING from the recorded value. Recorded: motor-related corollary discharge in auditory cortex — note: a second reading, verbatim-verified, disagreeing with the value on the record. Not applied - a person decides. Quotation withheld because this record is not cleared for redistribution. contradicts → the disinhibitory mechanism proposed for locomotion-dependent increases in visual cortical responses (ref. 38), the negative-rescaling account of state-dependent auditory cortical changes (ref. 23) and presynaptic depression from state-dependent thalamic activity (ref. 30) Quotation withheld because this record is not cleared for redistribution. builds-on → the prior anatomical finding that the M2-to-auditory-cortex projection is almost completely ipsilateral (ref. 20) Quotation withheld because this record is not cleared for redistribution. extends → observations of movement-related modulation of auditory cortex in monkeys and humans (refs. 1, 10, 11, 18, 37), for which a direct motor-cortical role had not been tested Quotation withheld because this record is not cleared for redistribution. contradicts → sensory reafference and peripheral masking as explanations for movement-related auditory suppression Quotation withheld because this record is not cleared for redistribution. distinguishes-from → the disinhibitory account of locomotion-driven gain increases in visual cortex differs in: THE AXIS IS THE CIRCUIT MECHANISM, WITH BOTH NAMED. 'This mechanism contrasts with A DISINHIBITORY MECHANISM implicated in locomotion-dependent increases in visual cortical responses, WITH A parallel negative rescaling of excitatory and inhibitory synaptic drive that has been advanced to account for STATE-DEPENDENT CHANGES.' Two accounts of behaviour-driven cortical change that predict opposite things about inhibition - so a result reported as 'state-dependent modulation' is compatible with either until the inhibitory drive is measured. Quotation withheld because this record is not cleared for redistribution. extends → anesthetized-mouse work showing motor cortical synapses suppress tone-evoked auditory responses Quotation withheld because this record is not cleared for redistribution. supports → corollary discharge accounts described across species from insects to humans Quotation withheld because this record is not cleared for redistribution. builds-on → anatomical tracing showing the M2-to-auditory projection is almost entirely ipsilateral Quotation withheld because this record is not cleared for redistribution. PV+ —causes→ excitatory neurons PV+ excitatory neurons strength of the relation: 1 · note: SIGN: suppressive, and the firing order M2 then PV then excitatory matches the proposed direction Audit 2026-09-28: DOUBTFUL - read against its full span and kept, but the span reports PV+ rates rising while excitatory rates fell; causes is loose here. Quotation withheld because this record is not cleared for redistribution. presynaptic depression —operationalised-as→ onset slope presynaptic depression onset slope strength of the relation: 1 · note: CRITERION, and the assay was VALIDATED FIRST: 20 Hz stimulation was shown to change the slope before the absence of a change was claimed as a null Quotation withheld because this record is not cleared for redistribution. visual cortex —contrasted-with→ auditory cortex visual cortex auditory cortex strength of the relation: 1 · note: SIGN REVERSAL: the same manipulation raises gain in one sensory cortex and lowers it in the other Quotation withheld because this record is not cleared for redistribution. t-test t-test Quotation withheld because this record is not cleared for redistribution. Kolmogorov-Smirnov test Kolmogorov-Smirnov test Quotation withheld because this record is not cleared for redistribution. significance level (alpha) significance level (alpha) Quotation withheld because this record is not cleared for redistribution. ANOVA ANOVA Quotation withheld because this record is not cleared for redistribution. interaction effect interaction effect Quotation withheld because this record is not cleared for redistribution. standard deviation standard deviation Quotation withheld because this record is not cleared for redistribution. percentile threshold percentile threshold Quotation withheld because this record is not cleared for redistribution. linear regression / slope linear regression / slope Quotation withheld because this record is not cleared for redistribution. linearly related linearly related Quotation withheld because this record is not cleared for redistribution. Just before and during locomotion, head movements, grooming and other movements, auditory cortical excitatory neurons showed less variable membrane potentials and a slight depolarization. Quotation withheld because this record is not cleared for redistribution. These membrane potential changes began on average more than 200 ms before locomotion started and persisted about as long after it ended. Quotation withheld because this record is not cleared for redistribution. Because the cortical changes precede movement onset by hundreds of milliseconds, they cannot be caused by sensory reafference from the movement, and could reflect a motor-related signal. Quotation withheld because this record is not cleared for redistribution. Unlike visual cortex, where locomotion boosts responses, tone-evoked synaptic responses of auditory cortical excitatory neurons were significantly reduced during movement. Quotation withheld because this record is not cleared for redistribution. Roughly 60 percent of the movement-related suppression of tone-evoked responses originates within the auditory cortex itself rather than upstream, since optogenetically evoked thalamocortical responses were suppressed in proportion to tone responses. Quotation withheld because this record is not cleared for redistribution. The rising slope of thalamocortical EPSPs was unchanged between movement and rest, ruling out presynaptic depression of thalamic terminals as the cause of suppression. Quotation withheld because this record is not cleared for redistribution. The movement-related membrane potential change reversed near -72 mV, close to the chloride equilibrium potential reported for mouse auditory cortical pyramidal neurons. Quotation withheld because this record is not cleared for redistribution. Around movement, PV+ and other fast-spiking interneurons in auditory cortex increased their firing while putative excitatory neurons decreased theirs. Quotation withheld because this record is not cleared for redistribution. The inhibitory neurons' firing rose several hundred milliseconds before movement onset and before excitatory cells dropped below baseline, consistent with inhibition leading the suppression. Quotation withheld because this record is not cleared for redistribution. Excitatory neurons in secondary motor cortex increased their firing about 870 ms before movement onset, earlier than any of the auditory cortical changes. Quotation withheld because this record is not cleared for redistribution. Optogenetically activating M2 axon terminals in the auditory cortex of a resting mouse reproduced the movement signature: reduced membrane potential variability, reduced tone-evoked responses and slight depolarization. Quotation withheld because this record is not cleared for redistribution. The terminal-activation effect was not an indirect antidromic one: it survived pharmacological silencing of M2 cell bodies with TTX. Quotation withheld because this record is not cleared for redistribution. The auditory cortical change began within 7 ms of terminal stimulation, faster than the roughly 12 ms antidromic conduction time back to M2, again excluding an indirect route. Quotation withheld because this record is not cleared for redistribution. Silencing ipsilateral M2 restored rest-like membrane potential dynamics in auditory cortex within about 70 ms of laser onset. Quotation withheld because this record is not cleared for redistribution. Tones presented after M2 silencing, while the mouse was still moving, showed a strong (~40 percent) recovery of tone-evoked responses. Quotation withheld because this record is not cleared for redistribution. auditory cortical excitatory neurons are suppressed before and during movement, due in part to increased activity of local PV+ interneurons Quotation withheld because this record is not cleared for redistribution. the change led locomotion by more than 200 ms and outlasted it by about as much Quotation withheld because this record is not cleared for redistribution. tone-evoked synaptic responses were suppressed during movement, opposite to the visual cortex Quotation withheld because this record is not cleared for redistribution. PV and other fast-spiking cells increased firing before movement while excitatory cells decreased Quotation withheld because this record is not cleared for redistribution. the firing order was PV at -805 ms, other inhibitory cells at -605 ms and excitatory cells at -490 ms relative to movement onset Quotation withheld because this record is not cleared for redistribution. M2 cells defined by their projection to auditory cortex behaved like the general M2 population Quotation withheld because this record is not cleared for redistribution. activating M2 terminals in resting mice reproduced the movement-like dynamics Quotation withheld because this record is not cleared for redistribution. silencing ipsilateral M2 restored rest-like dynamics within about 70 ms, while contralateral silencing did nothing until movement stopped Quotation withheld because this record is not cleared for redistribution. APPORTIONED, NOT EXCLUDED: about 60 percent of the suppression arises inside auditory cortex, measured from the slope relating optogenetic to tone suppression Quotation withheld because this record is not cleared for redistribution. ASSAY VALIDATED BEFORE THE NULL: high-frequency stimulation was shown to reduce EPSP onset slope before the absence of such a change during movement was claimed Quotation withheld because this record is not cleared for redistribution. CONTROL NULL: EPSP onset slope did not differ between movement and rest, so thalamic terminals are not depressed during movement Quotation withheld because this record is not cleared for redistribution. CONFOUND EXCLUDED TWO WAYS: the terminal-activation effect survived TTX silencing of M2 somata and was faster than antidromic propagation Quotation withheld because this record is not cleared for redistribution. DECOUPLING EXPERIMENT: with ipsilateral M2 silenced the cortex returned to a rest-like state while the mouse was still moving, and tones then recovered about 40 percent of their response Quotation withheld because this record is not cleared for redistribution. the decoupling separates the neural state from the movement itself and shows the state controls the gain Quotation withheld because this record is not cleared for redistribution. silencing M2 in a resting mouse slightly enhanced tone responses, so even baseline M2 activity is mildly suppressive Quotation withheld because this record is not cleared for redistribution. corollary discharge signals corollary discharge signals Quotation withheld because this record is not cleared for redistribution. M2 ACtx cells M2 ACtx cells Quotation withheld because this record is not cleared for redistribution. corollary discharge corollary discharge Quotation withheld because this record is not cleared for redistribution. onset slope onset slope Quotation withheld because this record is not cleared for redistribution. antidromic antidromic Quotation withheld because this record is not cleared for redistribution. movement movement Quotation withheld because this record is not cleared for redistribution. laser stimulation laser stimulation Quotation withheld because this record is not cleared for redistribution. membrane potential variability membrane potential variability Quotation withheld because this record is not cleared for redistribution. peak tone-evoked response peak tone-evoked response Quotation withheld because this record is not cleared for redistribution. body temperature body temperature Quotation withheld because this record is not cleared for redistribution. membrane potential membrane potential Quotation withheld because this record is not cleared for redistribution. onset slope onset slope Quotation withheld because this record is not cleared for redistribution. locomotion locomotion Quotation withheld because this record is not cleared for redistribution. slope = 0.6 — Linear relation between suppression of optogenetically evoked and tone-evoked responses, implying ~60% of suppression is cortex-local Quotation withheld because this record is not cleared for redistribution. >200 ms — Average lead time by which auditory cortical membrane potential changes precede locomotion onset Quotation withheld because this record is not cleared for redistribution. −805 ms for PV+ cells, −605 ms for VGAT+ cells, and −490 ms for excitatory cells — Times relative to movement onset at which each cell population's firing rate changed Quotation withheld because this record is not cleared for redistribution. −870 ms — Time relative to movement onset at which M2 excitatory neuron firing increased Quotation withheld because this record is not cleared for redistribution. ~ −72 mV — Reversal potential of the movement-related membrane potential change, near the chloride equilibrium potential Quotation withheld because this record is not cleared for redistribution. <7 ms — Latency of auditory cortical change after M2 terminal stimulation, versus ~12 ms antidromic propagation time Quotation withheld because this record is not cleared for redistribution. ~500 ms — Delay after light onset at which silencing M2 arrested the animal's movement Quotation withheld because this record is not cleared for redistribution. ~40 percent — Recovery of tone-evoked response when ipsilateral M2 was silenced during ongoing movement Quotation withheld because this record is not cleared for redistribution. 14.25 min — Mean duration of the intracellular recordings in freely behaving mice Quotation withheld because this record is not cleared for redistribution. n = 37 cells from 11 mice — Sample for the treadmill comparison of membrane potential variance at rest versus movement Quotation withheld because this record is not cleared for redistribution. p = 8e-9 — Significance of the drop in tone-evoked voltage area from rest to movement Quotation withheld because this record is not cleared for redistribution. more than 200 ms — how far the auditory cortical change precedes locomotion onset Quotation withheld because this record is not cleared for redistribution. about 60 percent — share of movement-related suppression arising locally in auditory cortex Quotation withheld because this record is not cleared for redistribution. -72 mV — reversal potential of the movement-related change, near the chloride equilibrium Quotation withheld because this record is not cleared for redistribution. under 7 ms against about 12 ms — onset of the terminal-activation effect against antidromic propagation time Quotation withheld because this record is not cleared for redistribution. about 40 percent — recovery of tone-evoked responses when M2 is silenced during ongoing movement Quotation withheld because this record is not cleared for redistribution. about 70 ms — delay before ipsilateral M2 silencing restored rest-like cortical dynamics Quotation withheld because this record is not cleared for redistribution.

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